Integrated Transcriptomic and DNA Methylation Analysis Identifies KRT6B and CHI3L2 as Candidate Shared Biomarkers of Psoriasis and Cutaneous Melanoma

Background: Different studies have drawn inconsistent conclusions on whether psoriasis increases the risk of cutaneous melanoma (CM). Although shared gene expression or methylation pathways between the two diseases have been independently reported, suggesting a potential molecular basis for their comorbidity, whether expression and methylation synergistically contribute to their pathogenesis remains unclear. Therefore, this study aimed to identify common methylation-regulated genes (co-MRGs) as potential biomarkers for the association between psoriasis and CM. Methods: Transcriptomic and DNA methylation data of psoriasis and CM, comprising 53 cases and 55 normal controls in total, from GEO and ArrayExpress were used as the main dataset. Differential expression and differential methylation analyses were performed on the main dataset using limma and DMRcate; co-MRGs were further identified. TCGA-GTEx data (472 CM cases and 326 normal controls) served as the external validation dataset to validate the expression regulation of the identified co-MRGs in CM. Network analyses were based on the main dataset; immune infiltration and survival analyses were based on the validation dataset; and IHC analyses were based on the HPA database. Results: Three co-MRGs ( KRT6B, CHI3L2 , and TSPAN8 ) were identified. KRT6B was hypomethylated/upregulated in psoriasis but hypermethylated/downregulated in CM, with enrichment in epidermal development and keratinization. CHI3L2 was hypomethylated and upregulated in both, exhibiting superior diagnostic performance (AUC = 0.867). TSPAN8 was hypermethylated/downregulated in both. KRT6B trended toward poor CM prognosis, whereas CHI3L2 high expression correlated with better survival. HPA-based IHC validation confirmed differential expression of KRT6B and CHI3L2 . Conclusion: This study identified two novel promising candidate co-MRG biomarkers, KRT6B and CHI3L2 , providing preliminary evidence for a shared molecular link between psoriasis and CM. However, limitations remain, as psoriasis and CM data were derived from separate datasets, and further experimental validation is required.